It has been found that there is an association between stress and disease occurrence in animals (T. Molitor and L. Schwandtdt, "Role Of Stress On Mediating Disease In Animals", Proc. Stress Symposia: Mechanisms, Responses, Management. Ed., N. H. Granholm, South Dakota State University Press, Apr. 6-7, 1993). Further it has been suggested that stress can lead to a compromised immune system. (T. Molitor and L. Schwandtdt, "Role Of Stress On Mediating Disease In Animals", Proc. Stress Symposia: Mechanisms, Responses, Management. Ed., N. H. Granholm, South Dakaota State University Press, Apr. 6-7, 1993/ Morrow-Tesch J. L. et al. 1996 J. Therm. Biol. 21(2):101-108) This can have significant effect on populations of animals such as commercial livestock including cattle, pigs, poultry, horses, and fish, wherein stress can be related to growth inhibition, infertility, and decreased milk or egg production (where applicable). It has been shown that the peripartum period or periparturition, in animals is a period of stress. (L. G. Johnson, "Temperature Tolerance, Temperature Stress, and Animal Development", Proc. Stress Symposia: Mechanisms, Responses, Management. Ed., N. H. Granholm, South Dakaota State University Press, Apr. 6-7, 1993; J. J. McGloner, "Indicators Of Stress In Livestock And Implications For Advancements In Livestock Housing", Proc. Stress Symposia, : Mechanisms, Responses, Management. Ed., N. H. Granholm, South Dakaota State University Press, Apr. 6-7, 1993; T. Molitor and L. Schwandtdt, "Role Of Stress On Mediating Disease In Animals", Proc. Stress Symposia: Mechanisms, Responses, Management. Ed., N. H. Granholm, South Dakaota State University Press, Apr. 6-7, 1993; M. J. C. Hessing et al, "Social Rank And Disease Susceptibility In Pigs", Vet Immunol. Immunopath 43:373-387, 1994; F. Blecha, "Immunoligcal Reactions Of Pigs Regrouped At Or Near Weaning", Am. J. Vet. Res. 46(9): 1934-1937, 1985; D. L. Thompson et al., "Cell Mediated Immunity In Marek's Disease Virus-Infected Chickens Genetically Selected For High and Low Concentrations Of Plasma Corticosterone", Am. J. Vet. Res. 41(1):91-96, 1980; Kehrli, H. E. et al., 1989a & b, Am. J. Vet. Res. 50(2):207 and 215).
Impairment of bovine host defense during the peripartum period may be associated with high concurrent disease occurrence. Impaired resistance may be due to endocrine factors associated with metabolic and physical changes occurring during gestation, parturition and lactation (Smith et al., 1973; Guidry et al., 1976; Burton et al., 1993). Infectious diseases of the peripartum period include mastitis, metritis and pneumonia. Metabolic and some reproductive diseases also predominate during this period and include retained placenta, milk fever, ketosis, and displaced abomasum. Mastitis is the most economically relevant disease. Estimated annual losses from mastitis are $35 billion (U.S) worldwide (Giraudo et al. 1997), $2 billion (U.S.) in the United States (Harmon, 1994) and $ 17 million (Can.) in Canada ($140-300 Can./cow) (Zhang et al., 1993).
Mastitis is an inflammation of the mammary gland characterized by local and systemic responses (Burvenich et al., 1994). Mastitis can be clinical or subclinical, when signs are not directly observable, but somatic cell counts in milk (SCC) increase and overall production performance decreases. Mastitis is caused by a number of Gram positive and Gram negative bacteria which are either major or minor pathogens. Major pathogens induce the greatest compositional changes in milk and have the greatest economic impact (Harmon, 1994). They include Staphylococcus aureus, Escherichia coli, Streptococcus agalactiae, Klebsiella spp., and others, while minor pathogens include coagulase negative staphylococci, and Corynebacterium bovis. The incidence of udder infection and clinical mastitis is usually highest at parturition and during early lactation (Smith et al., 1985). Coliforms such as E. coli and Klebsiella are the most common major pathogen during this period. Since coliform mastitis is difficult to treat, natural defence mechanisms of the mammary gland have been investigated in pursuit of control procedures (Burvenich et al., 1994). Coliform mastitis may be peracute and fatal, or subclinical. Most commonly it is acute clinical mastitis, with local and systemic signs of disease. Coliforms are Gram-negative microorganisms from the family Enterobacteriaceae which include important species from the genera Escherichia, Klebsiella, Enterobacter, Citrobacter and Proteus (Harmon, 1994; Kremer et al., 1994). The structure of the cell wall of coliform bacteria plays an important role in the virulence of the bacteria and subsequently in the pathogenesis of mastitis. The cell wall of E. coli has an inner cytoplasmic membrane, a peptidoglycan layer, an outer membrane that consists of two layers: a phospholipid protein layer and an outer lipopolysaccharide layer (LPS), and finally some strains possess an additional capsular polysaccharide layer. The LPS layer has three components: the O-specific polysaccharide chain, a polysaccharide core, and lipid A. Lipid A mediates the biological properties of LPS (endotoxin). Endotoxemia causes clinical signs of disease including high fever, drowsiness, appetite loss, dehydration, loss in milk production, cardiovascular failure, shock and often death (Kremer et al., 1994; Burvenich et al., 1994). Factors which contribute to susceptibility to mastitis include the complex environment (pasture, bedding, cleanliness of holding areas), management (milking practices, antibiotic therapy during lactation and dry-off) and physical trauma to the teat and/or udder (Cullor, 1995).
Various attempts have been made to develop vaccines against S. aureus as a treatment for mastitis, but without success. Vaccines have included toxoid, protein A, capsule and fibronectin in varying combinations and concentrations (reviewed by Sordillo, 1995). While these preparations may reduce the severity and duration of mastitis, new infections are not prevented. Inclusion of capsular polysaccharide in vaccine preparation slightly reduced the rate of new infection (Watson and Schwartskoff, 1990). More recently, the combination of a crude extract of S. aureus exopolysaccharides and inactivated unencapsulated S. aureus and Streptococcus spp. in a vaccine decreased incidence of intramammary infections caused by S. aureus (Giraudo et al., 1997). Newer vaccines against environmental coliforms contain rough or R-mutants of E. coli or Salmonella typhimurium. The surface core antigens of these mutants induces formation of cross-protective antibody that provides protection against various gram-negative diseases of animals including mastitis and calf scours. (Parker et al., 1994). These vaccines decrease incidence and severity of clinical disease but do not affect prevalence of coliform infections (Sordillo, 1995).
Direct selection for disease resistance may be done either by selecting the most disease-resistant breeding stock under normal environmental conditions, or by challenging the breeding stock with specific pathogens (Hutt, 1959). Indirect selection is based on identification of reliable indirect markers of disease resistance (Detilleux et al., 1993). Phenotypic indicators include morphological markers (eg. eye margin pigmentation in bovine infectious keraconjunctivitis), physiological markers (eg. hemoglobin type in malaria), and innate or immune response traits (eg. PMN function, antibody response and CMI). Genotypic indicators include candidate genes (eg. MHC genes, Ig genes, TcR genes), and anonymous molecular genetic markers (eg. RFLPs, tandem repeats loci, microsatellite loci) (Detilleux et al., 1993).
Experiments using immune response variation as selection criteria have been successful at directing response to be high or low (Biozzi et al., 1968; Ibanez et al., 1980; Siegel et al., 1980; Van der Zijpp et al., 1983; and Mallard et al., 1992). The continuous distribution antibody response suggests that response is under multigenic control (Puel and Mouton, 1996) and that characteristic quantitative antibody responsiveness is controlled by several independently segregating loci (Stiffel et al., 1987). The first selection experiment using antibody response following immunization was reported in guinea pigs assortatively mated for five generations. The immunogen used was diphtheria anatoxin and the immune responses of progeny were progressively modified in upward and downward directions (Shiebel, 1943). A similar experiment was conducted using rabbits selected for two generations based on antibody produced to Streptococcus sp. (Eichmann et al., 1971). A more extensive examination of antibody response variability in mice was demonstrated by Biozzi et al. (1979). Several independent selective matings were carried out with mice for antibody responsiveness to sheep red blood cells (SRBCs). SRBCs are multideterminant antigens which are strongly immunogenic in all strains of mice (Puel and Mouton, 1996). Assortative mating of mice with extreme phenotypes in upward or downward directions were repeated for successive generations until maximal divergence of the two lines was achieved (Biozzi et al., 1972). The relevance of this dichotomy pertains to the ability of mice to mount strong responses, either antibody or cell mediated immune response, to extra or intra cellular organisms. The low line (L line) was determined to be more resistant than the high line (H line) to intra-cellular organisms such as Salmonellae, Yersinia, Mycobacteria, and Brucellae, and when the macrophage provides the dominant defensive barrier. The H line was more resistant to extracellular microorganism including Pneumococcus, Klebsiella, Plasmodia, and Trypanosoma. The major genetic modification which explained differences between these selected lines was at the level of the macrophage. Antigen was observed to be slowly catabolized and persisted on the macrophage membrane of the H line mice, whereas it was rapidly destroyed in L line macrophages. Selection of chickens based on antibody response to SRBC has also demonstrated variation and the consequent divergence of high and low lines of chickens (Siegel and Gross, 1980; Van der Zijpp et al., 1983; Pinard et al., 1992). Antibody response to SRBC and chicken erythrocytes was similarly evaluated in guinea pigs, which diverged to high and low immune response lines after successive selection for 8 generations (Ibanez et al., 1980). Yorkshire pigs selected using estimated breeding values (EBVs) for both antibody and cell mediated immune response, were reported to diverge into high and low immune response lines (Mallard et al., 1992). The maximum divergence of high and low responses were observed between generation 1(G.sub.1) and 3 (G.sub.3) with little or no response to selection after generation 4 (G.sub.4) (Mallard et al., 1997). Although a few studies have examined the effect that selecting for milk production has on various innate and immune response parameters, no breeding studies have been conducted using immune response variation as selection criteria.
Selective breeding of cattle for resistance to mastitis using somatic cell count (SCC) is currently under evaluation. Current industry trends favour a low somatic cell count in milk secretions. A SCC that is too low may be detrimental to innate mechanisms of resistance to mastitis and therefore must be used with caution. Genetic correlation between SCC and mastitis vary, but values are mainly positive (r=0.81; Madsen, 1989; r=0.3, Weller et al., 1996). SCC is now considered the primary trait used to evaluate susceptibility to mastitis which enables indirect selection for resistance to mastitis (Shook, 1994; Dekkers et al., 1998). Selection based on occurrence of clinical mastitis is unreliable since it is not routinely recorded, it has complex aetiology, and observations on the occurrence and severity of mastitis are subjectively evaluated by producers. Several records on SCC are available through dairy herd improvement corporations which provide a substantial database from which to determine estimated breeding values for SCC. SCC and its logarithmic transformation, SCS, have higher heritability (h.sup.2 =ranging between 0.10-0.12) (Emmanuelson et al., 1988; Banos and Shook, 1990; Boettcher et al., 1992) than clinical mastitis (h.sup.2 =0.03) (Emmanuelson, 1988; Madsen, 1989). However, low heritability estimates of SCS, in contrast to some production traits, indicate that SCS is not influenced to a greater degree by environmental factors. Low heritabilities suggest that SCS and mastitis will respond more slowly to genetic improvement than milk yield (Shook, 1993; Boettcher et al., 1992). Research conducted in Ontario by Dekkers and Burnside (1994) evaluating estimated transmitting abilities (ETAs) for linear somatic cell score (LSCS) indicated that daughters of the poorest sires had double the average SCC (transformed from LSCS) of daughters of the best sires, and, sires whose daughters had a higher LSCS tend to have more mastitis problems. This research indicated that, although adding LSCS to genetic selection will reduce genetic progress for production by &lt;2 percent, it will also slow down the current genetic deterioration of resistance to mastitis. Its inclusion would be relevant since there would be lower treatment and other related mastitis costs and there would be an increase in the revenue per cow per year by 0.3 to 1.0 percent, despite a slight decrease in milk sales. While there is some benefit to using SCS as a selection tool, it is not as heritable as some aspects of immune response phenotype. Antibody response to ovalbumin (OVA) in dairy calves was reported by Burton et al. (1989) to be moderately heritable (h.sup.2 =0.48), and in contrast to SCS may be more promising as a selection tool for improved inherent disease resistance (Burton et al., 1989).
Dekkers et al. (1996a) recently developed a sire index called the total economic value index (TEV) which includes economically weighted traits of importance. It includes production, herd life and udder health. Production accounts for 64% of the TEV, herd life for 26% and udder health, which includes SCS, accounts for 10% of the TEV. While production still is the most economically important, more emphasis can now be placed on the costs associated with mastitis by evaluating SCS. Once more heritable candidate markers of immune response are determined, more information about udder health could be added to the TEV.